Intermediates for the preparation of



United States Patent Ofitice A 3,058,992 Patented Oct. 16, 1962 Thepresent invention relates to new substituted tryptamine compounds of thegeneral formula:

where R represents an alkyl radical selected from the group consistingof ethyl and methyl and, more particularly, to2-(6'-methoXy-3'-indolyl)-l-propylamine and 2-( 6'-methoxy3'-indolyl)-l-butylamine, and to the acid addition salts of thesecompounds, and to processes of preparing the same.

It is an object of this invention to provide substituted tryptaminecompounds of the general formula:

?Ha NH:

In principle, the present invention relates to the tryptamine compoundsof the Formula I CH30 N NH2 where R represents an alkyl radical selectedfrom the group consisting of ethyl and methyl and to their acid additionsalts.

The processes of producing said substituted tryptamine compounds may beillustrated by the following reaction flow-sheets:

TABLE I CHO CHaO H Gila-NO:

$H O'HBO NO! III 1 It-Mg Halogen (1H1 OHSO NO:

(EH onto NH Or C2H5 TABLE II l GzH5Mg Halogeh TABLE II--Continued CHsOThese compounds are prepared, as shown in Table I which indicates thevarious reaction stages and the formulas of the intermediates obtainedthereby. Inprinciple, the process consists in reacting nitro methanewith 6-methoxy-3-formy1 indole of Formula 11 in an appropriate organicsolvent and in the presence of an organic base, as, for example, inbenzene containing piperidine.

The resulting reaction product, 2-(6'-methoxy-3-indoly1)-l-nitro etheneof Formula III is isolated from the reaction mixture and is condensedwith a Grignard reagent such as an ethyl magnesium halide or a methylmagnesium halide. Thereby the compound of Formula IV is obtained. Thecondensation is carried out in an inert anhydrous organic solvent suchas tetrahydrofuran at a temperature of from about C. to about 20 C.

The resulting reaction product of Formula IV is then reduced by means ofa mixed metal hydride in an anhydrous inert organic solvent at elevatedtemperatures. 'Reduction with lithium aluminum hydride intetrahydrofuran at reflux temperatures is preferred.

The amine of Formula I is purified by conversion into an insoluble acidaddition salt thereof, such as the picrate or the acetate, anddecomposing the latter according to conventional techniques.

According to another process, Compound I, where R=CH can be prepared asshown in'Table 11, which indicates the various reaction stages and theformulas of the intermediates obtained thereby.

. 6-methoxy indole of Formula V is reacted with a Grignard reagent suchas a lower alkyl magnesium halide and preferably an ethyl magnesiumhalide in a suitable solvent, preferably in a phenol ether such asanisole. The resulting 6-methoxy indolyl magnesium halide VI iscondensed with 1x 0101110 propionitrile at a low temperature.2-(6-methoxy -3'-indolyl) propionitrile of Formula VII is obtainedthereby. It is extracted from the reaction mixture and purified.Reduction of said compound is carried out by means of hydrogen in thepresence of a nickel catalyst and in alcoholic ammoniacal solution.Thereby, 2-(6'-methoxy-3-indolyl)-1-propylamine of Formula I (R=CH isobtained which is isolated and crystallized in the form of its slightlysoluble picrate. After decomposition of the picrate by the action of analkali metal hydroxide, the free amino compound is extracted by means ofmethylene chloride and is isolated from the'extract.

The following examples serve to illustrate the present inventionwithout, however, limiting the same thereto. More particularly, thenature of the reducing agent, the solvent employed, the extractingsolvent, and the like may be varied by those skilled in the art inaccordance with the principles set forth herein and in the claimsannexed hereto. 7 Y

The melting points given in the examples are instantaneous meltingpoints determined on the Maquenue block.

Example I PREPARATION OF 2-'(6M ETHOXY3'-INDOLYL)1- NITRO-ETHENE OFFORMULA III 120 g. of 6-methoxy-3-formyl indole of Formula II (preparedas described by D. G. Harvey and W. Robson, J. Chem. Soc., vol. 1938,page 97), 5,400 cc. of benzene, 38.4 cc. of piperidine, and 83.5 g. ofnitromethane are introduced into a flask provided with a condenserpermitting return of the distilled benzene to the reaction mixture andremoval of the water distilled thereby as azeotropic mixture withbenzene.

The reaction mixture is heated to boilingunder reflux for 6 hours.During this time 12 cc. of water are collected. The reaction mixture isthen allowed to cool and stand overnight. The resulting precipitate isfiltered off, dried at room temperature, and washed by triturating itwith benzene and vacuum filtering.

After drying 128 g. of 2-(6-methoxy-3'-indolyl)-1- nitro-ethene, FormulaIII, are obtained. This crude material, which has a melting point of 202C., is purified by recrystallization from ethanol. 63.5 g. areobtainedas first fraction, corresponding to a yield of 42.5%.

The 2-(6-methoxy-3'-indolyl)-l-nitro-ethene obtained in this manner,which has not been described in the literature, forms brick redprismatic crystals. It is soluble in acetone, tetrahydrofuran, and warmalcohol, and insoluble in vether, benzene and chloroform.

Analysis.C I-I ,O N molecular weight=2l8.21. Calculated: C, 60.54%; H,4.62%; O, 22.0%; N, 12.84%.

1 Found: 0, 60.5%; H, 4.9%; o, 22.3%; N, 12.8%.

7 Example II PREPARATION OF 2-(6 -\dETHOXY-3 -INDOLY L)-1- NITRO-PROPANE(IV RzcHs) iodide to 22.3 g. of magnesium, is placed in an ice bath in anitrogen atmosphere.

The addition of the intermediate nitro compound (compoundof Formula III)to the. Grignard reagent is eifected within one and a half hours in sucha manner that the temperature is kept between 15 C. and 20 C.

The reaction mixture is then. agitated for 4 hours and is treated with1,250 cc. of a saturated solution of ammonium chloride. Agitation iscontinued for another 15 minutes. The aqueous phase is decanted andextracted with ether. The combined ether extracts are washed with a 5%solution of sodium bisulfite and thereafter with water. 7

The washed ether extracts are dried over sodium sulfate, filtered, andthe filtrate is distilled in a vacuum until dry. The distillationresidue consists of 50 g. (about 93% yield) of2-(6'-methoxy-3-indolyl)-1-nitro-propane, IV (.R=CI-I It maybe used assuch, without further purification, in the next reaction step. This2-(6'-methoxy-3'- indolyl) -1-nitro-propane has not been describedpreviously in the literature.

Example 111 PREPARATION OF THE PICRATE OF 2 (6-METHOXY-3-INDOLYL)-l-PROPILAMINE (I; RzCHs) 50 g. of2-(6-methoxy-3-indolyl)-1-uitro-propane, IV (R=CH prepared according toExample II are dissolved in 1000 cc. of tetrahydrofuran and added to asolution containing 25 g. of lithium aluminum hydride in 750 cc. oftetrahydrofuran. During addition which requires about one and a halfhours, moderate refluxing is maintained. Heating is continued for 4hours and, after cooling, excess hydride is destroyed by adding water.The mixture is filtered and the precipitated alumina is washed withtetrahydrofuran. The wash waters are added to the filtrate which is thenevaporated to dryness in a vacuum. The residue is dissolved in methylenechloride and extracted with a 5% aqueous solution of acetic acid. Theacetic acid extracts are alkalized with a 5 N sodium hydroxide solutionuntil a pH of 10.0 is achieved and the alkaline extracts are againextracted with methylene chloride. The methylene chloride extracts aredried, filtered and evaporated to dryness in a vacuum.

25 g. of the crude compound of 2-(6-methoxy-3-indolyl)1-propylamine, I(R=CI-I are obtained and are converted into the picrate by dissolutionin 100 cc. of ethanol. The resulting solution is added to an alcoholicsolution of picric acid. Thereby the picric acid salt of the indolecompound of Formula I (R=CH is precipitated. The mixture is cooled withice for one hour, filtered, dried at room temperature and Washed bytnturating with ethanol and vacuum filtering.

After drying, 44.5 g. of the picrate of 2-(6'-methoxy-3-indole)-1-propylamine, I (R=CH of the melting point of 242 C. areobtained, corresponding to a yield of 48%. This salt has a vivid redcolor.

Example IV PREPARATION OF 2- GJIETHOXY S -INDOLYL) -1- NITRO-BUTANE, IV(R C2H An ether solution of ethyl magnesium halide is prepared from 289g. of ethyl iodide and 39 g. of magnesium. The solution is cooled to C.and 88 g. of 2- (6-methoxy-3'indolyl)-l-nitro-ethene, III, preparedaccording to Example I, and 1760 cc. of tetrahydrofuran are addedthereto with stirring and under an atmosphere of nitrogen. Addition of2-(6-methoxy-3'-indo1yl)-1- nitro-ethene to said ethyl magnesium halideis elfected in such a manner as not to exceed 20 C. and requires about 1/2 hours. The resulting mixture is stirred for 4 hours, whereafter 2 l.of a saturated solution of ammonium chloride are added. The mixture isagain stirred for minutes. The aqueous phase is decanted and extractedwith ether. The organic extracts are combined and washed with watercontaining 5% of sodium bisulfite and thereafter with pure water. Afterdrying over sodium sulfate and filtering the filtrate is distilled firstat atmospheric pressure and then in a vacuum until dry. 100 g. of abrown gum are obtained, consisting of 2-(6'-methoxy-3-indolyl)-1-nitrobutane, IV (R=C H The gum is used withoutfurther purification in the following reaction step.

This product is new.

Example V PREPARATION OF 2-(6-\IETHOXY-3-INDOLYL)-1 BUTYLAMINE PICRATE(I, R:C2H,,)

100 g. of 2-(6'-methoxy-3'-indolyl)-1-nitro-butane, IV (R=C H preparedaccording to the preceding example, in 2000 cc. of tetrahydrofuran areadded very slowly to 45 g. of lithium-aluminum hydride in 1500 cc. oftetrahydrofuran. The addition takes two hours and increases thetemperature of the reaction mixture to gently boiling under reflux dueto the vigorous reaction taking place thereby, which causesdiscoloration of the nitro compound. Boiling under reflux is continuedfor 4 hours. After cooling, excess hydride is destroyed by the additionof water. The alumina precipitate is filtered oil and washed withtetrahydrofuran. The filtrate and the wash liquors are combined andevaporated to dryness in a vacuum. The residue is dissolved in 1200 cc.of benzene. The benzene solution is extracted with a 5% aqueous aceticacid solution and the acetic acid extracts are rendered alkaline by theaddition of 300 cc. of 5 N sodium hydroxide solution. The aqueoussolution is then extracted with benzene and the benzene extracts aredried over potassium hydroxide pellets and evaporated to dryness in avacuum. The residue, a brown resin, weighs 53 g. It is dissolved in cc.of methanol. 55 g. of picric acid dissolved in 700 cc. of methanol areadded thereto. Crystallization is initiated by scratching. The mixtureis allowed to stand at room temperature for 30 minutes and is thencooled in ice for one hour. The resulting crystals are filtered off,washed with methanol, and dried. 47.5 g. of the brick red picrate of2-(6'- methoxy-3-indolyl)-1-butylarnine, I (R g s), are obtained;melting point: 223 C. The yield is 26% calculated for the compound ofFormula IV. A second crop of 10 g. can be recovered from the motherliquors, thus bringing the total yield to 31.9% of the theoreticalamount. This new compound is soluble in acetone and dimethyl formarnide,slightly soluble in alcohol, and insoluble in water, benzene andchloroform.

Analysis.-C H O N molecular weight=447.40. Calculated: C, 51.00%; H,4.73%; N, 15.65%; Found: C, 50.9%; H, 4.8%; N, 15.4%.

Example VI PREPARATION OF 2-(6-'VIETHOXY-3-INDOLYL)-1- BUTYLAMINEACETATE (I, RzCzHs) 2 g. of the raw amine of Formula I (R=C H preparedaccording to Example V, are dissolved in 20 cc. of benzene, 0.6 cc. ofacetic acid are added and the gum which is formed is triturated in thebenzene. The crystals thus produced are filtered off, washed by making apaste with benzene, and dried under vacuum. 2.3 g. of the acetate of 2(6'-methoxy 3' indolyl) 1 butylamine, I (R=C H are obtained; meltingpoint: 165 C. Yield: 90% of the theoretical yield. For purposes ofanalysis the acetate is recrystallized from ethyl acetate whereby,however, the melting point is not changed.

Analysis.C H O N molecular weight=278.35. Calculated: C, 64.73%; H,7.96%; O, 17.24%; N, 10.07%. Found: C, 64.9%; H, 7.9%; O, 17.3%; N,10.1%.

This new compound is obtained in the form of white prismatic crystals,soluble in water and hot ethyl acetate, slightly soluble in alcohol, andinsoluble in ether, benzene and chloroform.

Example VII PREPARATION OF 2-(GJIETHOXY-EV-INDOLYL)-1- BU'IYLAMINE OFFORMULA I (R:'C2H

To 305 mg. of the acetate, prepared according to the preceding example,in 30 cc. of water, dilute sodium hydroxide solution is added until themixture is clearly alkaline. It is then extracted with benzene. Theextracts are washed with water, dried over Na S0 and distilled todryness under vacuum. 240 mg. of a transparent amber yellow resinconsisting of the free base of 2-(6-nrethoxy-3-indolyl)-1-butylamine ofFormula I (R=C H are obtained. Yield: 93% of the theoretical yield. Thisproduct, which has not been previously described in the literature, issoluble in alcohol, benzene and methylene chloride, slightly soluble inether, and insoluble in water. It reacts with acetone. Its infraredspectrum confirms the assumed structure.

In place of tetrahydrofuran, used as inert organic solvent in ExamplesII and V, there may be employed other inert organic solvents, such asether.

In place of the picrate and the acetate, there may be chloride or,respectively, bromide.

' iodide in 32.5 cc.ro anisole.

produced other insoluble acid addition salts, suchas salts formed fromlower alkanoic acids, lower alkanedioic acids and polynitrophenolicacids and, in particular, the propionate, the butyrate, the oxalate, thetartrate, the succinate, for purifying the crude amine.

In place of ethyl or methyl magnesium iodide, used as condensationcompound, there may be employed the equimolecular amount of ethyl ormethyl magnesium Otherwise the procedure is the same as that describedin the preceding examples.

Example VIII 7 PREPARATION OF 2-(6-r\[ETHOXY-3-Il IDOLYL) PROPIONIIRILE(FORMULA WI 2.85 g. of magnesium are reacted with 20.5 g. of ethyl Afterformation of ethyl magnesium iodide is completed, the solution iscooledin an ice bath and a solution of 9.5 g. of 6-methoxy indole of Formula Vin 20 cent anisole warmed to about 40 C. is added dropwise thereto.. Thereaction mixture is stirred at room temperature for half an hour and iscooled to C. 12 g. of a-bromo propionitrile and '10 cc. of anisole areadded thereto. The mixture is stirred for 3 hours while cooling to 0 C.in the beginning. After the addition of 200 cc. of 10% aqueous aceticacid, the mixture is extracted with methylene chloride and the organiclayer 'is Washed successively with Water, a solution of sodiumbicarbonate, and water. Methylene chloride is distilled oil in a vacuumand the remaining anisole is distilled ed at a pressure of 0.2 mm. Thedistillation residue is a viscous product which consists substantiallyof 2-(6'- methoxy-3-indolyl) propionitrile of Formula VII. It may beused as such, without further purification, in the next reaction step.The compound has not yet been described in the literature. 7 7

Example IX PREPARATION OF THE PICRA'IE 2-(6-METHOXY-3'-INDOLYIi)-l-PROPYLAMINE (FORMULA I; RzCHs) The viscous compound obtainedaccording to the preceding example is dissolved in 150 cc. of ethanol..80 cc. of ethanol saturated with ammonia and 12 g. of Raney nickel areadded thereto. The air in the reaction vessel is removed by firstpassing nitrogen and then jhydrogen therethrough. The solution issubjected to the action of hydrogen for 7 hours while another 12 g. ofRaney nickel were added to the mixture after. 3 hours. The catalyst isfiltered oh and the solvent is distilled ofi in a vacuum. The residue istaken up with methylene chloride. The solution is extracted with 200 cc.of 10% aqueous acetic acid and then with 0 cc. of water. The aqueousextract is washed with methylene chloride and the aqueous layer isrendered alkaline by the addition of a concentrated sodium hydroxidesolution. The new substituted tryptamine compound is extracted from thealkaline reaction mixture by means of methylene chloride. The organiclayer is washed with a solution of sodium chloride and is evaporated todryness. The resulting residue is dis solved in 25 cc. of ethanol. Afteraddition of 100 cc. of an ethanolic solution of picric acid (5% picricacid), the reaction mixture is cooled. The resulting precipitate isfiltered off; The well crystallized and stable picrate of2-(6'methoxy-3-indolyl)-1-propylamine, I (R=CH of a reddish-orange coloris obtained thereby. The new compound is insoluble in ether, soluble inwarm ethanol and acetone and in cold dimethylformamide; The com:

pound has a melting point of 242 C, (with decomposition). The totalyield is 20% of the theoretical yield calculated for 6-methoxy indole ofFormula V.

Analysis.C H N O molecular weight=433.37. Calculated: C, 49.88%; H,4.42%; N, 16.16%; 0, 29.54%. Found: C, 50.0%; H, 4.5%; N, 16.0%; 0,29.4%.

This compound is identical with that prepared in Example III.

7 Example X PREPARATION OF 2-(6'-METHOXY-3'-INDOLYL)-1- PROPYLAMINE, I;RICHB 1 In order to prepare the free amine of Formula I; R=CH 1.5 g. ofthe picrate ofExamples III or IX are suspended in 100 cc. of methylenechloride and 20 cc.

of an 11.5% aqueous lithium hydroxide solution is added thereto. The twolayers are separated and the aqueous layer is extracted with methylenechloride. The com- 'bined organic solutions are washed successively witha mixture of a saturated lithium hydroxide solution and a saturatedsodium chloridesolution (1:1) and with a saturated sodium chloridesolution. After filtration, the organic solvent is evaporated in avacuum. 680 mg. of 2-(6 methoxy-3 indolyl)-l-propylamine of Formula I(R=CH are obtained in the form of a viscous oil (96% of the theoreticalyield). When treated with sodium nitroprusside, violet coloration takesplace, as is characteristic for primary aliphatic amines. The compoundis insoluble in water, slightly soluble in ether, and soluble inalcohol, chloroform, and methylene chloride. Its infrared spectrumcorresponds to the structure proposed for the compound. The compound hasnot yet been described in the literature. 7

As stated hereinahove, the new substituted tryptamine compoundsaccording to the present invention are useful intermediates in thesynthesis of physiologically active compounds of the reserpine series.'For instance, the new tryptamine compounds are converted into suchreserpins compounds by reaction with the dextrorotatory meth yl ester oflfi-carboxyl methyl-2,8-methoxy carbonyl-3a--methoxy-4,6-acetoxy-6fi-formyl cyclohexane in a neutral solvent. Theresulting condensation pro-duct is subjected to the action of potassiumborohydride in a lower alkanol and the 6-alkyl-1l,17oa-dimethoxyl6B-methoxy carbonyl- 185 -hydroxy 3 oxo 2,3 seco 20oz yohimbaneobtained thereby is esterified in l8-position by means of3,4,5-trimethoxy 'benzoic acid arr-hydride in the presence of a pyridinebase and triethylamine. 'On heating said 18'- ester compound inphosphorus oxychloride to cause ring closure and on reducing theresulting unsaturated quaternary ammonium compound by means of zinc inthe presence of perchloric acid and in a water miscible solvent,

6-alkyl reserpine is'obtained. The alkyl in th e'6 posi tion can beeither ethyl or methyl. It occurs in two isomeric forms. Reserpine-likecompounds can also be produced by condensing the methyl ester ofl/3-carboxy methyl 2B methoxy carbonyl- 3a methoxy 4,8-

acetoxy-6fl-forrnyl-cyclohexane as described by Woodward et al., J. Am.Chem. Soc. 78, 2023-5 (1956).

The substituted tryptamine compounds are of the general formula omowhereR represents an alkylradical selected from the group consisting of ethyland methyl and'are useful as antimetabolites.

It is known that the intestinal flora is constituted by of coli bacilliand related species. The coli bacilli secrete, in the intestinal tract,an enzyme named tryptophanase which catalyzes the formation of indoliccom- Intestinal media Trypto hanase Bacillus coli 1 p IndolicTryptophane compounds These indolic compounds are toxic and, in fact,responsible for a large number of intestinal disturbances.2-(6-methoxy-3'-indolyl)-1-propylamine and2-(6-n1ethoxy-3-indo1yl)-1-butylamine block the tryptophanase action ontryptophane by substituting themselves (antimetabolic action). Thisaction is distinct at a concentration of 0.1 g./liter which neithehinders the development of the coli bacilli nor at the same timemodifies the intestinal flora.

The present application is a continuation-in-part of our copendingUnited State patent applications, Serial No. 760,577, filed September12, 1958, in the name of Andr Allais; Serial No. 784,847, filed January5, 1959, in the name of Andr Allais; and Serial No. 797,887, :filedMarch 9, 1959, in both our names, all now abandoned.

Of course many changes and variations in the solvents used, the basicagents employed, the reaction conditions, temperature and duration, themanner of Working up and purifying the reaction products, and the like,may be made by those skilled in the art in accordance with theprinciples set forth herein and in the claims annexed hereto.

10 We claim: 1. A compound of the formula (EH2 OHKO N 02 Where Rrepresents an alkyl radical selected from the group consisting of ethyland methyl.

2. 2- 6'-methoxy-3 -indolyl )-1-nitro-butane.

3. 2-(6-methoXy-3'-ind0ly1)-1-mtro-propane.

4. 2-( 6-methoXy-3 '-indolyl) -propionitrile.

References Cited in the file of this patent UNITED STATES PATENTS2,804,462 Specter Aug. 27, 1957 2,814,625 Specter Nov. 26, 19572,883,384 Woodward Apr. 21, 1959 2,959,591 Petrzil'ka et a1. Nov. 8,1960 FOREIGN PATENTS 1,187,064 France Mar. 2, 1959 1,199,603 France June22, 1959 OTHER REFERENCES Abramovitch: J. Chem. 800., page 4601 (1956).Velluz et al.: Comptes Rendus, pages 1746-1748 (1958).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N003,058,992 October 16, 1962 Andr Allais et alu It is hereby certifiedthat error appears in the above numbered patent requiring correction andthat the said Letters Patent should read as corrected below.

Column 2, formula I, under TABLE I, lines 45 to 55, the formula shouldappear as shown below instead of as in the patent:

Signed and sealed this 30th day of April 1963.

EAL) 111G811: I RNEST W. SWIDER DAVID L. LADD .ttesting OfficerCommissioner of Patents

1. A COMPOUND OF THE FORMULA